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Food allergy has become a concern amongst mankind in the recent years. Individuals allergic to certain food have to practice abstinence towards these foods. No treatment or cure is currently available for food allergies and hence the only means to remain symptoms free is to avoid consumption of food that might trigger an allergic reaction. This brings about the burden of reading ingredient labels on every packaged food product they purchase to ensure their safety. Although this might be a demanding and time consuming task, serious attention has to be given to this issue as eating certain food can be life threatening to those with food allergies (Boyce et al., 2013).
Reports on cases of allergies have been on the rise. According to a recent statistic by the American Academy of Allergy Asthma and Immunology (AAAAI), 40% of the population worldwide is sensitized to foreign proteins in the environment. With regards to adverse immune responses to foods, approximately 5% of young children and 3% to 4% of adults in westernized countries are affected and it appears to have increased in prevalence. The factors responsible for this evident increase however, have not been identified (Sicherer et at., 2010).
Food related hypersensitivity; an abnormal physiologic response to a particular food (Taylor, 1987), findings from a 2009 to 2010 study of 38,480 children (those aged below 18) indicated that approximately 6% aged 0-2 years, 9% aged 3-5 years, 8% aged 6-10 years, 8% aged 11-13 years and 8.5% aged 14-18 years have a food allergy. Out of all these food allergic children, 38.7% of them have a history of severe reactions. The finding also illustrated that 30.4% of food allergic children have multiple food allergies. Peanut is the most prevalent allergen, followed by milk and then shellfish amongst the food allergic children (Bloom et al., 2010).
Food allergies are a significant public health issue worldwide and concerns about this form of allergy is ever growing. Food allergy in itself can be caused by many different forms of food which affect different age groups in different manners. For instance, in young children the most prevalent allergies are to foods such as cow's milk (2.5%), egg (1.3%), peanut (0.8%), wheat (approximately 0.4%), soy (approximately 0.4%), tree nuts (0.2%), fish (0.1%), and shellfish (0.1%). These foods, often mentioned as the "Big 8", are responsible for vast majority of IgE-mediated food allergies on a worldwide basis (FAO, 2011).
Approximately 80% of early childhood allergies to to milk, egg, soy, and wheat are resolved by school age. Seafood, peanut and tree nut allergies on the other hand are considered as permanent allergies. Thus, adults are more likely to to have allergies to shellfish (2%), peanut (0.6%), tree nuts (0.5%), and fish (0.4%). These are staple foods for most countries worldwide and are often used in preparing food. Besides, traces of these foods are also found in various processed foods. For this matter, food allergy sufferers rely on accurate labeling in order to avoid allergens and the resulting allergic reaction (Sicherer and Sampsom, 2006).
Unlike the "big 8", fruit and vegetable allergy is generally more common in older children and young adults (approximately 5%). Most people with a fruit or vegetable allergy tend to continue to be allergic as they grow older. The one exception is potato allergy in young children, which tends to resolve with time. Cases on fruit and vegetable allergies are also on the rise (Madsen, 1997). According to an allergies expert Dr. Pamela Ewan, the rise in cases appears to be outstripping even peanut allergies. She also stated: "It is a bit like the peanut allergy was the epidemic of the 1990s (BBC News). I think fruit and vegetables are becoming the epidemic now." This proves that fruit and vegetable allergies are becoming a concern among those who consumes vegetables and fruits. Sadly, there are limited studies on fruit and vegetable allergens as compared to other food such as the "big 8".
Correspondingly, little information is currently available on the allergens in local Malaysian fruits and the fate of these possible digestion-resistant allergens. These digestion-resistant proteins or peptides could have immunologically active epitopes that could sensitize individuals upon exposure. Moreover, a better understanding of allergen stability could be used to assess if these potentially stable proteins and peptides could be used as critical components in development of specific ELISAs for diagnosis of food allergies and potentially used a targets for development of immunotherapy treatment of food allergy.
This review will distinguish between different adverse reactions to foods and define true food allergies and their prevalence among children and adult populations, with a particular focus on fruit allergy. This review will also focus on the mechanism of action of these allergens invitro i.e. gastric and intestinal digestion.
2.2 : FOOD SENSITIVITIES
Food sensitivities are classified as abnormal physiological responses to foods. It circumscribes a wide range of adverse reactions to foods and they are further classified as food allergies and food intolerances (Figure 1.1). Health conditions such as gastrointestinal illnesses or drug therapy may cause food sensitivities (Berstad et al., 2005). There are a few distinct differences between food intolerances and food allergies out of which the most predominant is the engagement of an individual's immune system in allergic reactions. An allergic reaction in general causes an immediate and clear reaction, such as swelling, rashes or difficulty in breathing whereas the symptoms of food intolerances are not as quick. Some of the symptoms of food intolerance includes indigestion, gas, bloating, vomiting, lethargy, headaches, migraines and joint pains (Mary, 2001).
Food allergies exist when an individual's immune system reacts negatively to a particular food be it in the form of solid or liquid. It can be further categorized as immediate hypersensitivity (IgE-mediated) reactions, or delayed hypersensitivity (cell-meditated) reactions (Berstad, 2005). In general, food sensitivities as a whole is often falsely interpreted. Almost all adverse reactions to foods are perceived as being a form of food allergy among the general public. This is far from true as food sensitivities can be allergies, food intolerances etc. (Nelson and Ogden, 2008; Madsen 1997). For that matter, this review and research focuses on IgE-mediated allergic reactions.
Primary Food Sensitivity
(No involvement of Immune system)
(Involvement of Immune system)
Metabolic food disorders
Cell Mediated (delayed hypersensitivity reactions)
Ig-E mediated (Immediate hypersensitivity reactions)
Figure 1.1: Primary Food Sensitivity Reactions Classification (Adapted Steve and Susan, 2001)
2.2.1 : FOOD INTOLERANCE
Food intolerances can be defined as an adverse reaction with allergy-like symptoms, but with no proven involvement of the immune system (Madsen, 1997). Food intolerances are often caused by the presence of certain genetic defects of the susceptible individual, or intrinsic factors of a particular food (Kelesidis et al., 2010). Those with food intolerances can usually tolerate minute quantities of the offending food or food component in their diets without experiencing adverse reactions. Therefore, food intolerances can be controlled simply by lowering the intake of the food causing the illness whereas the best measure for individuals with food allergies is strict avoidance of foods known to cause allergic reactions. In addition, food intolerances are further classified as metabolic food disorders, anaphylactoid reactions, or idiosyncratic reactions (Steve and Susan, 2001).
22.214.171.124 : METABOLIC FOOD DISORDERS
Metabolic food disorders can be defined as adverse reactions resulting from the body's inability to metabolize a particular food or its components. This condition can either be inherited genetically or acquired through transitory factors (Steve and Susan, 2001). Lactose intolerance and favism are some of the common metabolic food disorders. Lactose intolerance is caused by an inadequate production of the enzyme lactase or Î²-galactosidase in the brush-border of the intestinal mucosa (JianFeng et al., 2013). Consequently, lactose which is the primary sugar in milk and other dairy products, cannot be hydrolyzed into the individual monosaccharides, galactose and glucose. The unhydrolyzed lactose cannot be absorbed by the epithelial cells of the small intestine and it reaches the colon, where colonic bacteria metabolize the lactose resulting in the production of CO2, H2, and H2O (JianFeng et al., 2013; Vernia et al., 2010).
Lactose intolerance is estimated to affect two thirds of the world adult population with variable frequencies between racial and ethnic groups. The frequency exceeds 50% in South America, Africa, and Asia. In the US, the frequency among Caucasians is 15%, 53% among Mexican-Americans, and 80% among the African American population. As for Australia and New Zealand, about 6 to 9% of the population is affected with lactose intolerance. Only about 2% of Scandinavians are affected by lactose intolerance, but the frequency reaches 70% in Sicily. Moreover, the frequency of lactose intolerance is observed to be greater with advancing age. This is predominantly because of the natural decrease in intestinal lactase activity (JianFeng et al., 2013).
Common symptoms of lactose intolerance include bloating, abdominal cramping, flatulence, and frothy diarrhea (Vernia et al., 2010). Lactose tolerance test is the most frequent method used for its diagnosis. In this test, a fasting individual is orally given 50mg of lactose followed by blood glucose level monitoring whereby levels of glucose exceeding 25mg/dl are perceived as normal. The most common treatment for lactose intolerance up to date is simply the avoidance of dairy products containing lactose. Yogurt and acidophilus milk on the other hand have been shown to be tolerated most likely because of the presence of bacteria containing Î²-galactosidase (Vesa et al., 2000; Taylor and Hefle, 2002).
Another example of metabolic food disorder is Favism which results in an acute hemolytic anemia. Favism is believed to be caused by exposure to fava beans or the inhalation of pollen from the Vicia faba plant. The symptoms of favism encompasses pallor, fatigue, dyspnea, nausea, abdominal and/or back pain, fever, and chills. Some of the severe symptoms may include hemoglobinuria, jaundice, and renal failure. Recovery is rapid and spontaneous due to the self-limiting characteristics of the disease (Steve and Susan, 2001).
Like lactose intolerance, favism is caused by inherited genetic deficiency which results in the inability to produce an enzyme, glucose-6-phopsphate dehydrogenase (G6PDH), in the red blood cells in the case of favism. This enzyme regulates the levels of glutathione and nicotinamide adenine dinucleotide phosphate which in turn prevents oxidative damage of the red blood cells. Fava beans are known to contain vicine and covicine which activ ly damages the erythrocytes of glucose-6-phopsphate dehydrogenase (G6PDH) deficient individuals (Taylor and Hefle, 2006a).
Among all enzymatic defects in humans, favism is the most prevalent. It is estimated to affect 100 million people worldwide. The highest frequency has been seen among Oriental Jewish communities, the African American population, and individuals in the Mediterranean region, the Middle East, China, and certain African populations. An assay for enzymatic activity on isolated red blood cells has been commonly used as a diagnostic tool for favism (Steve and Susan, 2001).
126.96.36.199 : ANAPHYLACTOID REACTIONS
Anaphylactoid reactions to particular foods involve the release of mediators from mast cells and basophils such as histamine without intervention the individual's immune system. However, the mechanism behind the release of these mediators remains unresolved. The substances in these foods which cause the release of these mediators have yet to be identified and hence the proof for the existence of anaphylactoid reactions remains contentious. Strawberries and chocolates are some of the foods which are associated with causing anaphylactoid reactions (English and Brown, 2007). Currently, the only treatment for anaphylactoid reactions is avoidance of the offending food because diagnosis of anaphylactoid reactions remains a challenge (English and Brown, 2007; Sicherer and Donald, 2004).
188.8.131.52 : IDIOSYNCRATIC REACTIONS
Idiosyncratic reactions can be defined as the adverse reactions to foods affecting certain individuals. Much like Anaphylactoid reactions, the mechanism behind the adverse reactions is still unknown (Sicherer and Donald, 2004). Sulfite-induced asthma, tartrazine-induced asthma, and Chinese restaurant syndrome are some of the examples associated with these reactions caused by a particular food or residues of the food (Bennis, 1998).
The symptoms associated with these reactions may range from minor to severe and life-threatening reactions. As of now, the only dependable diagnostic tools for this type of disease are challenge tests. Sulfite-induced asthma is one of the well known idiosyncrasies identified to occur in some individuals. Besides occurring naturally in food, sulfites are also normally used as additives in the food processing industry. Sulfite is very useful in controlling enzymatic and non-enzymatic browning, stopping microbial growth, conditioning dough, preventing oxidation, and as a bleaching agent of certain products. For this reason it is highly favorable to the food processing industry (Steve and Susan, 2001) . Despite the fact of its unresolved mechanism of action, sulfite ingestion induced asthma affects approximately 5% of steroid-dependent asthmatic individuals (Bennis, 1998). For this reason, the level of added sulfites in foods must be declared on food labels if it exceeds 10 ppm as protection for sulfite-sensitive consumers (Steve and Susan, 2001).
2.2.2 : FOOD HYPERSENSITIVITY
184.108.40.206: THE IMMUNE SYSTEM
The human immune system can be defined as the constellation of responses to attacks of foreign particles from outside the body. The main function of the immune system is to protect the host from harmful substances and pathogenic microorganisms via a range of cells and molecules competent in recognizing and eliminating potential infectious agents. The mechanism of the immune system is divided into four main parts i.e. immunological recognition, immune effector functions, immune regulation, and generation of immunological memory. This involves both the innate and adaptive immune systems (Chaplin, 2003).
The innate immunity is responsible in providing the first line of defense against an infection. This system however has certain shortcomings. In particular, it lacks the ability to identify specific pathogens and provide the specific protective immunity (memory) that prevents reinfection. The innate immune system employs cells and molecules which have a broad specificity to pathogens in order to combat infections. These cells encompass granulocytes, macrophages, mast cells, dendritic cells, and natural killer cells (Stuart et al., 2010). Granulocytes are made up of white blood cells called neutrophils, eosinophils, and basophils (Figure 1.2).
Cells of immune system image.jpg
Figure 1.2 : Cells of the immune system (Adapted from Kenneth, 2012)
When the innate defense mechanism is breached by an infection, an adaptive immune response is triggered which is competent of selectively eliminating specific foreign agents (antigens). B lymphocytes (B cells) and T lymphocytes (T cells) are the major cells involved in the adaptive immune response. B Cells are responsible for the creation of antibodies that circulate in blood plasma and lymph (Figure 1.3). These antibodies bind specifically to foreign agents and inactivate them (viruses and microbial toxins) by inhibiting their ability to bind to receptors on host cells (Francisco and Hans, 2010). Antibodies or immunoglobulins, are proteins made up of two large heavy chains and two small light chains large which gives it a Y-shape. Humans have five types of antibody which are IgA, IgD, IgE, IgG, and IgM. They differ in biological properties i.e. each are specific to different kinds of antigens. The antibody responses are also called humoral immunity. In contrast, cytolytic T cells, have the ability to target and kill cells expressing certain surface markers (Andersson et al., 2010).
Figure 1.3: B cell mechanism of action (Adapted from Addison Wesley Longman, Inc.)
In addition, the adaptive immune responses can be further classified into T cell-mediated immune responses and B-cell humoral immune responses. Antigen recognition sets off a cascade of reactions where a naÃ¯ve T cell differentiates into several different classes of effector T cells which are responsible for cell-mediated responses by the host. Cytotoxic T cells can either eliminate infected cells directly or indirectly depending on the type of effector TH cell. The humoral immune responses alternatively guards the extracellular spaces between cells. It involves activated B cells that are capable of differentiating into antibodies that secretes plasma cells. (Edel et al., 2001).
Under certain circumstances, harmless antigen such as pollen, food, and drugs can cause the immune system to induce an inappropriate response by the immune system. These inappropriate and undesirable responses are referred to as a hypersensitivity reaction and are sometimes denoted as allergic reactions. They can provoke mild to life-threatening responses (Chaplin, 2003).
Abnormal immune responses to harmless substances include several mechanisms that can be classified into 4 main categories (Table 1). The different types of reaction are classified based on the effector molecules that are produced during the reaction. Type I, type II, and type III hypersensitivity reactions consist of humoral immune responses, which are mediated by the interaction of antigen-antibody complex. Type IV hypersensitivity reactions in contrast employ the T cell-mediated responses that can be divided into three groups, and are frequently denoted to as delayed-type hypersensitivity since symptoms may not develop for several hours to days after the initial antigen exposure (Murphy et al., 2008).
Cell or matrix-associated antigen
Mast cell activation
Table 1.1: Adapted and altered from Murphy et al., 2008.
Food hypersensitivity is defined as "an abnormal immunological response to a particular food or food component, usually a naturally occurring protein" and has been viewed as an emerging public health problem. The most important mechanism involved in food hypersensitivities is the IgE-mediated hypersensitivity (immediate hypersensitivity reaction) which specifically recognize certain allergenic proteins in foods followed by the cell-mediated hypersensitivity which requires an interaction between a particular food antigen and sensitizes T lymphocytes (Berstad, 2005).
220.127.116.11 : CELL MEDIATED HYPERSENSITIVITY
Cell mediated hypersensitivity can be defined as the delayed hypersensitivity reactions with onset of symptoms generally occurring within 6 to 24 or more hours after ingestion of the offending food. It includes protein-induced enterocolitis, celiac disease, food-protein induced proctitis, protein-induced enteropathy, allergic eosinophilic gastroenteritis and esophagitis (Steve and Susan, 2001). Compared to IgE-mediated response, the immune responses attributed to this form of hypersensitivity are far less understood. The main example of a delayed hypersensitivity is celiac disease, also known as celiac sprue or gluten-sensitive entheropathy. Celiac disease is basically a malabsorption syndrome which is triggered by a permanent intolerance to gluten in genetically predisposed individuals (Stoven et al., 2012; Martucci et al., 2002).
The Celiac disease, according to the epidemiological studies is found to be higher in women than men with 2.5:1 ratio. The frequencies in the US and Europe is estimated to be in range between 1:100 and 1:150 individuals. Moreover, the frequency of the disease is found to be higher (4-12%) in first degree relatives of patients with the celiac disease (Lionetti et al., 2012).
The Celiac disease is characterized by localized inflammatory reactions in the intestinal tract (Lionetti et al., 2012; Martucci et al., 2002). The symptoms are different depending on age group and represent those of non-IgE mediated hypersensitivities which are illustrated by chronic diarrhea, abdominal pain, vomiting, malnutrition, weight loss, chronic constipation, failure to thrive, and dermatologic or respiratory symptoms (Stoven et al., 2012).
The inflammatory response is caused by wheat gluten and similar proteins of barley and rye that are resistant to endoluminal proteolytic digestion, due to a high amount of proline and glutamine in their amino acid structure. These Pro and Gln rich peptides can pass through the mucosal layer of the intestinal epithelial cells either by moving between tight junctions or by direct absorption, where they get deamidated by tissue transglutaminase 2, an enzyme secreted by the intestinal cells. Once inside the lamina propria, the deamidated gluten peptides can come into contact with antigen presenting cells (Paavola et al., 2012; Stoven et al., 2012; Martucci et al., 2007).
The most reliable form of diagnosis of celiac disease requires both small bowel biopsy and a positive resolution of symptoms once the patient conform to a gluten-free diet for an extended period. Currently, diagnosis for this disease also includes several non-invasive serologic tests (Olén et al., 2011).
At present, treatments for celiac disease remains scarce and the only alternative for patients are to commit to a strict gluten-free diet accompanied with dietary supplementation and other immunosuppressant therapies. Nevertheless, there are progresses in the development of potential therapies for celiac disease which is sturdily portrayed by the oral enzyme therapy that can degrade gluten into nonhazardous components (Paavola et al., 2012; Stoven et al., 2012; Olén et al., 2011; Martucci et al., 2007).